The present invention relates to new alkaloid derivatives, to processes for their production and to novel pharmaceutical compositions and dosage forms containing them. More specifically, the present invention relates to the therapeutic use of new salts of indole alkaloids that are effective in the treatment of syndromes affecting the elderly, particularly conditions that are related to changes in cerebral metabolism and reduced blood flow.
Many naturally occurring alkaloids, synthetic alkaloid analogues and derivatives of naturally occurring alkaloids and alkaloid analogues have extensive use in pharmacology for treatment of numerous pathological conditions and also for inducing desired physiological states in healthy patients. Examples include the alkaloids used in the cardiovascular field, in obstetrics and in neurology.
In general alkaloids are nitrogenous bases that occur in plants, particularly those of the families Papaveraceae, Apocynaceae, Papilonaceae, Ranunculaceae and Solanaceae. Most alkaloids are characterised by the presence of one or more nitrogen atoms located in a heterocyclic ring system. General discussions of alkaloids are to be found in standard text books and particular reference is to be made, for example, to the Chapter entitled "Alkaloids" in Organic Chemistry, 3rd Edition, Fieser, L. F. and Fieser, M., Reinhold Publishing Corporation, 1956 and the Chapter entitled "Alkaloids and other Amino-Acid Derivatives" in The Biosynthesis of Natural Products, Bu'Lock, J. D., McGraw-Hill Publishing Company Limited, 1965 and in particular to "The Alkaloids Chemistry and Physiology, R. H. F. Marske and H. L. Holmes (Eds.), Academic Press Inc., Publishers.
Naturally occurring alkaloids generally have substituent groups which are susceptible to modification and derivatisation and synthetic alkaloids and derivatives of naturally occurring alkaloids may be prepared by, for example, subjecting a naturally occurring alkaloid to one or more of the following chemical modifications:
(i) esterification, PA0 (ii) hydrolysis of an ester group, PA0 (iii) salification, PA0 (iv) conversion of a primary, secondary, or tertiary amino group respectively to a secondary, tertiary or quaternary amino group PA0 (iv) epimerisation, PA0 (vii) conversion of a salt to a free base, PA0 (ix) etherification of a hydroxy group, PA0 (x) conversion of an etherified hydroxy group to a free hydroxy group. PA0 Alk represents a cation derived from said pharmacologically active, naturally occurring or synthetic alkaloid, or alkaloid derivative, PA0 PA represents a phosphatidic acid or a mixture of different phosphatidic acids, and PA0 x:y is from 2:1 to 1:2.
The term "synthetic alkaloid analogues and derivatives of naturally occurring alkaloids" as used herein is intended to include naturally occurring alkaloids which have been subjected to one or more of the above modification steps (i) to (x).
Typical alkaloids in widespread use include vincamine and apovincamine and their derivatives, raubasine, apocuanzine, nicergoline and hydergin.
A disadvantage of available alkaloids and alkaloid derivatives is that they generally are highly hydrophilic and consequently are not readily converted into dosage forms which are adapted to partition into the lipid phase. Also available dosage forms are not readily adapted for transcutaneous administration nor for formulation into convenient sustained release forms.